Project Summary The primary cilium is a microtubule-based cell organelle that functions as the cell antenna that senses and transduces environmental signals to regulate intracellular processes and cell behaviors. Genetic mutations that cause ciliary dysfunction have been identified in more than a dozen human disorders collectively called ciliopathies. Ciliopathies manifest as a constellation of clinical features in nearly every major body organ, highlighting the essential role of the primary cilium in development and homeostasis. To date, there are still major gaps in our knowledge about how primary cilia are formed, maintained and function in signal transduction, and the mechanisms associated with ciliary dysfunction are yet to be fully elucidated. Recently, several inactivating mutations in the human ICK gene were identified as the causative mutations for human ciliopathies, such as endocrine-cerebro-osteodysplasia (ECO) syndrome and short rib polydactyly syndrome (SRPS). The human ICK (intestinal cell kinase) gene encodes a serine/threonine protein kinase and we generated an Ick mutant mouse model that carries the same loss-of-function single residue substitution (R272Q) as human ECO syndrome patients. Mice homozygous for the Ick R272Q mutation replicate ECO developmental phenotypes and die around birth due to respiratory distress. The Ick mutant lung exhibits significant airspace deficiency in the primitive alveoli associated with an abnormal increase in interstitial mesenchymal differentiation during lung sacculation. This mouse has elongation of primary cilia and enhanced ciliary Hedgehog signaling and autophagy. These cellular changes likely contribute to the ECO disease phenotype and prompted our hypothesis that ICK-dependent signaling negatively regulates ciliogenesis and autophagy. We propose three specific aims to test this hypothesis. Aim 1 will determine novel ICK-dependent mechanisms that regulate ciliary structure and signaling. Aim 2 will determine how a novel ICK-Scythe signaling axis negatively regulates autophagy. Aim 3 will determine whether increased ciliary signaling and autophagy promote myofibroblastic cell phenotype in ECO ciliopathy. The significance of this project derives from human ciliopathies that have an expanding disease spectrum with devastating clinical outcomes. Our studies are innovative in elucidating new mechanisms of aberrant signal transduction that are still poorly understood. We will use a novel ciliopathy mouse model. The impact of our research includes new insights into the process of EMT (epithelial to mesenchymal transition) that relates to a variety of human pathologies. In addition, we will contribute new fundamental knowledge on the regulation of ciliary structure, signaling and autophagy.